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bioRxiv2017

Beyond The Linear Genome: Comprehensive Determination Of The Endogenous Circular Elements In C. elegans And Human Genomes Via An Unbiased Genomic-Biophysical Method

Investigations aimed at defining the 3-D configuration of eukaryotic chromosomes have consistently encountered an endogenous population of chromosome-derived circular genomic DNA, referred to as extrachromosomal circular DNA (eccDNA). While the production, distribution, and activities of eccDNAs remain understudied, eccDNA formation from specific regions of the linear genome has profound consequences on the regulatory and coding capabilities for these regions. High-throughput sequencing has only recently made extensive genomic mapping of eccDNA sequences possible and had yet to be applied using a rigorous approach that distinguishes ascertainment bias from true enrichment. Here, we define eccDNA distribution, utilizing a set of unbiased topology-dependent approaches for enrichment and characterization. We use parallel biophysical, enzymatic, and informatic approaches to obtain a comprehensive profiling of eccDNA in C. elegans and in three human cell types, where eccDNAs were previously uncharacterized. We also provide quantitative analysis of the eccDNA loci at both unique and repetitive regions. Our studies converge on and support a consistent picture in which endogenous genomic DNA circles are present in normal physiological DNA metabolism, and in which the circles come from both coding and noncoding genomic regions. Prominent among the coding regions generating DNA circles are several genes known to produce a diversity of protein isoforms, with mucin proteins and titin as specific examples.

genomics↗

bioRxiv2017

High-resolution analysis of spatiotemporal virulence gene regulation during food-borne infection with Escherichia coli O157:H7 within a live host

Food-borne infection with enterohemorrhagic Escherichia coli (EHEC) is a major cause of diarrheal illness in humans, and can lead to severe complications such as hemolytic uremic syndrome. Cattle and other ruminants are the main reservoir of EHEC, which enters the food-chain through contaminated meat, dairy, or vegetables. However, how EHEC transitions from the transmission vector to colonizing the intestinal tract, and how virulence-specific genes are regulated during this transition, is not well understood. Here, we describe the establishment of a vertebrate model for food-borne EHEC infection, using the protozoan Paramecium caudatum as a vector and the zebrafish (Danio rerio) as a host. At 4 days post fertilization, zebrafish have a fully developed intestinal tract, yet are fully transparent. This allows us to follow intestinal colonization, microbe-host cell interactions, and microbial gene induction within the live host and in real time throughout the infection. Additionally, this model can be adapted to compare food- and water-borne infections, under gnotobiotic conditions or against the backdrop of an endogenous (and variable) host microbiota. Finally, the zebrafish allows for investigation of factors affecting shedding and transmission of bacteria to naive hosts. High-resolution analysis of EHEC gene expression within the zebrafish host emphasizes the need for tight transcriptional regulation of virulence factors for within-host fitness.\n\nIMPORTANCEEnterohemorrhagic Escherichia coli (EHEC) is a food-borne pathogen which can cause diarrhea, vomiting and in some cases, severe complications such as kidney problems in humans. Up to 30% of cattle are colonized with EHEC, which can enter the food-chain through contaminated meat, dairy and vegetables. In order to control infections and stop transmission, it is important to understand what factors allow EHEC to colonize its hosts, cause virulence and aid transmission. Since this cannot be systematically studied in humans, it is important to develop animal models of infection and transmission. We developed a model which allows us to study food-borne infection in zebrafish, a vertebrate host that is transparent and genetically tractable. Using the zebrafish host, we can follow the bacterial infection cycle in real time, and gain important information regarding bacterial physiology and microbe-host interactions. This will allow us to identify potential new targets for infection control and prevention.

microbiology↗

bioRxiv2017

Power and shift invariant detection of dynamically coupled networks (PSIICOS) from non-invasive MEG data

MEG reflects electrical activity of neuronal assemblies that coalesce and decoalesce in time providing for massively parallel and dynamic flow of information exchange in the brain. There is a growing evidence that our behavior is mediated by simultaneous activity of several interacting and simultaneously active cortical networks. Not only the location of network nodes but also the temporal profiles of such interaction are of interest. The existing methods are primarily concerned with proposing novel measures of synchrony to be applied to the cortical region activity signals extracted from the MEG data using beamforming or other spatial filtering approaches.\n\nIn this work we propose to render the task of estimating network topology and temporal profiles as a source estimation problem but in the space of interacting topographies. The proposed point of view has a number of benefits as it allows to use the wealth of techniques and intuition accumulated in the community when dealing with source estimation problems. Operating in the interacting topographies space we first propose subspace projection method to significantly reduce the spatial leakage effect in the cross-spectral matrix. We then use subspace matching metrics to extract a set of networks with their synchronicity profiles that explain the variance in the sensor space cross-spectral matrix, much like regular dipoles and their activations explain the variance in the regular evoked responses.\n\nThe preliminary results of application of this method to a simple self-paced voluntary finger movement paradigm comparing allowed to observe functional coupling between primary motor and supplementary motor area and establish that this coupling can be characterized with near-zero phase delay between the oscillatory activity of these two regions. This observed synchrony pattern is physiologically plausible and is in agreement with the current hypothesis about the neural mechanics of the motor acts.

neuroscience↗

bioRxiv2017

Pooled CRISPR interference screens enable high-throughput functional genomics study and elucidate new rules for guide RNA library design in Escherichia coli

Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology provides potential advantages in high-throughput functional genomics analysis in prokaryotes over previously established platforms based on recombineering or transposon mutagenesis. In this work, as a proof-of-concept to adopt CRISPR/Cas9 method as a pooled functional genomics analysis platform in prokaryotes, we developed a CRISPR interference (CRISPRi) library consisting of 3,148 single guide RNAs (sgRNAs) targeting the open reading frame (ORF) of 67 genes with known knockout phenotypes and performed pooled screens under two stressed conditions (minimal and acidic medium) in Escherichia coli. Our approach confirmed most of previously described gene-phenotype associations while maintaining < 5% false positive rate, suggesting that CRISPRi screen is both sensitive and specific. Our data also supported the ability of this method to narrow down the candidate gene pool when studying operons, a unique structure in prokaryotic genome. Meanwhile, assessment of multiple loci across treatments enables us to extract several guidelines for sgRNA design for such pooled functional genomics screen. For instance, sgRNAs locating at the first 5% upstream region within ORF exhibit enhanced activity and 10 sgRNAs per gene is suggested to be enough for robust identification of gene-phenotype associations. We also optimized the hit-gene calling algorithm to identify target genes more robustly with even fewer sgRNAs. This work showed that CRISPRi could be adopted as a powerful functional genomics analysis tool in prokaryotes and provided the first guideline for the construction of sgRNA libraries in such applications.\n\nImportanceTo fully exploit the valuable resource of explosive sequenced microbial genomes, high-throughput experimental platform is needed to associate genes and phenotypes at the genome level, giving microbiologists the insight about the genetic structure and physiology of a microorganism. In this work, we adopted CRISPR interference method as a pooled high-throughput functional genomics platform in prokaryotes with Escherichia coli as the model organism. Our data suggested that this method was highly sensitive and specific to map genes with previously known phenotypes, potent to act as a new strategy for high-throughput microbial genetics study with advantages over previously established methods. We also provided the first guideline for the sgRNA library design by comprehensive analysis of the screen data. The concept, gRNA library design rules and open-source scripts of this work should benefit prokaryotic genetics community to apply high-throughput mapping of defined gene set with phenotypes in a broad spectrum of microorganisms.

microbiology↗

bioRxiv2017

Ophiuroid Phylotranscriptomics Enables Discovery Of Novel Echinoderm Representatives Of Bilaterian Neuropeptide Families And Reconstruction Of Neuropeptide Precursor Evolution Over ~270 Million Years

BackgroundNeuropeptides are a diverse class of intercellular signaling molecules that mediate neuronal regulation of many physiological and behavioural processes, including feeding, reproduction and locomotion. Recent advances in genome/transcriptome sequencing are enabling identification of neuropeptide precursor proteins in species from a growing variety of animal taxa, providing new insights into the evolution of neuropeptide signaling. Here we report a phylo-transcriptomic analysis of neuropeptide precursors in over fifty species of brittle stars (Class Ophiuroidea; Phylum Echinodermata).\n\nResultsDetailed analysis of transcriptome sequence data from three brittle star species, Ophionotus victoriae, Amphiura filiformis and Ophiopsila aranea, enabled the first comprehensive identification of neuropeptide precursors in ophiuroids. Representatives of over thirty bilaterian neuropeptide precursor families were identified, some of which occur as paralogs (e.g. thyrotropin-releasing hormone, corticotropin-releasing hormone, cholecystokinin, somatostatin and pedal peptide). Furthermore, homologs of endothelin/CCHamide, eclosion hormone, neuropeptide-F/Y and nucleobinin/nesfatin were discovered here in a deuterostome/echinoderm for the first time. The majority of ophiuroid neuropeptide precursors contain a single copy of a neuropeptide, but several precursors comprise multiple copies of identical or non-identical, but structurally-related, neuropeptides. Here we performed an unprecedented investigation of the evolution of neuropeptide copy-number over a period of ~270 million years by analysing sequence data from over fifty ophiuroid species, with reference to a robust phylogeny. Interestingly, the number of neuropeptide copies in the majority of precursors was constant across all the species examined, but examples of clade-specific losses/gains of neuropeptides were also observed.\n\nConclusionsWe report here the most comprehensive analysis to date of neuropeptide precursors in the phylum Echinodermata, with novel representatives of several bilaterian neuropeptide families discovered for the first time in echinoderms. Furthermore, analysis of precursor proteins comprising multiple copies of identical or related neuropeptides across ~270 million years of ophiuroid evolution indicates that the composition of neuropeptide \"cocktails\" is functionally important, but with plasticity over long evolutionary time scales.

neuroscience↗

bioRxiv2017

The closed-loop pathways of signaling molecules

The pathways of signaling molecules are important to understanding how signaling molecules regulate physiological function and also in predicting the pathological development which is important to therapeutic strategy, however the thorough knowledge of these pathways is still lack. In this paper, we used the big data concept to analyze the pathways of signaling molecules and categorize these molecules into five groups according to their origin and effect on the five organs of heart-spleen-lung-kidney-liver. Heart group includes IGF, Ang and Mg; spleen group includes ANP, aldosterone, retinoic acid and ghrelin; lung group includes FGF7, VEGF, ascorbic acid and HIF; kidney group includes calcitonin, PTHrP, Wnt and NO; and liver group includes EPO, renin, SOD, AKR and GSH. We found that each group of molecules have assisting effect on the other organ in the order of heart-spleen-lung-kidney-liver-heart, and have regulating effect on the other organ in the order of heart-lung-liver-spleen-kidney-heart. Moreover, the pathways of molecules of each group also follow these two arrangements, in which the pathways of molecules form a closed-loop that may lead to new therapeutic strategies.

bioinformatics↗

bioRxiv2017

A Versatile Genetic Tool For Post-Translational Control Of Gene Expression With A Small Molecule In Drosophila melanogaster

Several techniques have been developed in Drosophila to control gene expression temporally. While some of these techniques are incompatible with existing GAL4 lines, others suffer from side effects on physiology or behavior. Here, we describe a method of post-translational temporal control of gene expression which is compatible with the current library of transgenic reagents. We adopted a strategy to regulate protein degradation by fusing a protein of interest to a destabilizing domain (DD) derived from the Escherichia coli dihydrofolate reductase (ecDHFR). Trimethoprim (TMP), a stabilizing small molecule, binds to DD and blocks degradation of the chimeric protein. With a GFP-DD reporter, we show that this system is effective across different tissues and developmental stages in the fly. Notably, feeding flies with TMP can increase the expression level of GFP-DD up to 34 times in a dosage-dependent and reversible manner without altering the lifespan or behavior of the animal. To broaden the utility of our method, we engineered GAL80-DD flies that can be crossed to the available GAL4 lines to control the temporal pattern of gene expression with TMP. We also developed an inducible recombinase, FLP-DD, for high-efficiency sparse labeling and intersectional lineage analysis. Finally, we demonstrated the utility of the DD system in manipulating neuronal activity of sensory neurons. In summary, we have developed a system to control in vivo gene expression levels with negligible background, large dynamic range, and in a reversible manner, all by feeding a small molecule to Drosophila melanogaster.

genetics↗

bioRxiv2017

Modulation Of Type IV Pili Phenotypic Plasticity Through A Novel Chaperone-Usher System In Synechocystis sp 6803

Controlling the transition from a multicellular motile state to a sessile biofilm is an important eco-physiological decision for most prokaryotes, including cyanobacteria. Photosynthetic and bio geochemically significant cyanobacterium Synechocystis sp. PCC6803 (Syn6803) uses Type IV pili (TFP) for surface-associated motility and light-directed phototaxis. We report the identification of a novel Chaperone-Usher (CU) system in Syn6803 that regulate secretion of minor pilins as a means of stabilizing TFP morphology. These secreted minor-pilins aid in modifying TFP morphology to suit the adhesion state by forming cell to surface contacts when motility is not required. This morphotype is structurally distinct from TFP assembled during motile phase. We further demonstrate by examining mutants lacking either the CU system or the minor-pilins, which produce aberrant TFP, that are morphologically and functionally distinct from wild-type (WT). Thus, here we report that in Syn6803, CU system work independent of TFP biogenesis machinery unlike reported for other pathogenic bacterial systems and contributes to provide multifunctional plasticity to TFP. cAMP levels play an important role in controlling this switch. This phenotypic plasticity exhibited by the TFP, in response to cAMP levels would allow cells and cellular communities to adapt to rapidly fluctuating environments by dynamically transitioning between motile and sessile states.\n\nSignificance of this workHow cyanobacterial communities cope with fluctuating or extreme environments is crucial in understanding their role in global carbon and nitrogen cycles. This work addresses the key question: how do cyanobacteria modulate external appendages, called Type IV pili, to effectively switch between motile and sessile biofilm states? We demonstrate that cells transition between forming strong cell-surface interactions indispensable for biofilm formation to forming cell-cell interactions that allow for coordinated movement crucial for social motility by functional/ structural modification of same TFP appendage. The second messenger, cAMP and a Chaperone-Usher secretion are indispensible to achieve these structural modifications of TFP and control the complex phenotypic transition. We have uncovered a strategy that Syn6803 has evolved to deal with molecular decision-making under uncertainty, which we call phenotypic plasticity. Here we demonstrate how a single motility appendage can be structurally modified to attain two antagonistic functions in order to meet the fluctuating environmental demands.

microbiology↗

bioRxiv2017

Neural Correlates of human cognitive abilities during sleep

Inter-individual differences in sleep spindles are highly correlated with \"Reasoning\" abilities (problem solving skills; i.e., the ability to employ logic, identify complex patterns), but not Short Term Memory or Verbal abilities. Simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) have revealed brain activations time-locked to spindles (e.g., thalamic, paralimbic, and motor cortical areas)-yet the functional significance of inter-individual differences in spindle-related brain activation remains to be investigated. Using EEG-fMRI during sleep, we identified, for the first time, the neural activation patterns time-locked to spindles that are correlated with cognitive abilities. Similar to previous studies, activations time-locked to spindles were observed in thalamocortical circuitry and basal ganglia regions. Importantly, spindle-related activation in a subset of these regions were specifically related to inter-individual differences in Reasoning, but not STM or Verbal abilities. These results may help elucidate the physiological mechanisms which support the function of sleep for the capacity for reasoning.

neuroscience↗

bioRxiv2017

Supercoiling DNA locates mismatches

We present a method of detecting sequence defects by supercoiling DNA with magnetic tweezers. The method is sensitive to a single mismatched base pair in a DNA sequence of several thousand base pairs. We systematically compare DNA molecules with 0 to 16 adjacent mismatches at 1 M monovalent salt and 3.5 pN force and show that, under these conditions, a single plectoneme forms and is stably pinned at the defect. We use these measurements to estimate the energy and degree of end-loop kinking at defects. From this, we calculate the relative probability of plectoneme pinning at the mismatch under physiologically relevant conditions. Based on this estimate, we propose that DNA supercoiling could contribute to mismatch and damage sensing in vivo.

molecular biology↗

bioRxiv2017

Tolerance To PVY Infection In Potato Is Conditioned By Perturbation Of Small RNA-Gibberellin Regulatory Network

Potato virus Y is the most economically important potato viral pathogen. We aimed at unraveling the roles of small RNAs (sRNAs) in the complex immune signaling network controlling the establishment of tolerant response of potato cv. Desiree to the virus. We constructed a sRNA regulatory network connecting sRNAs and their targets to link sRNA level responses to physiological processes. We discovered an interesting novel sRNAs-gibberellin regulatory circuit being activated as early as 3 days post inoculation before viral multiplication can be detected. Increased levels of miR167 and phasiRNA931 were reflected in decreased levels of transcripts involved in gibberellin biosynthesis. Moreover, decreased concentration of gibberellin confirmed this regulation. The functional relation between lower activity of gibberellin signaling and reduced disease severity was previously confirmed in Arabidopsis-virus interaction using knockout mutants. We further showed that this regulation is salicylic acid-dependent as the response of sRNA network was attenuated in salicylic acid-depleted transgenic counterpart NahG-Desiree expressing severe disease symptoms. Besides downregulation of gibberellin signaling, regulation of several other parts of sRNA network in tolerant Desiree revealed similarities to responses observed in mutualistic symbiotic interactions. The intertwining of different regulatory networks revealed shows how developmental signaling, disease symptom development and stress signaling can be balanced.

plant biology↗

bioRxiv2017

Induction of Reproductive Behaviors by Exogenous Hormones in Captive Southern Rocky Mountain Boreal Toads, Anaxyrus boreas boreas

Loss of reproductive viability, physiologically and/or behaviorally, can have profound effects on the fitness of a captive population and conservation efforts. The southern rocky mountain (SRM) population of the boreal toad has declined over the past 35 years, making captive breeding necessary to protect and augment the species in the wild. In recent years, a notable reduction in the incidence of amplexus and viable offspring from the captive breeding population has been observed. Hormone treatment protocols to stimulate gamete release in males and females are established in this species and in vitro fertilization has been performed successfully. However, successful hormone stimulation of reproductive behaviors and natural fertilization has not been well documented. During the breeding season of 2012, 24 males and 24 female toads were selected from a population of over 600 captive animals. Both sexes were treated with Human chorionic gonadotropin (hCG) and Gonadotropin Releasing Hormone (GnRH) or phosphate buffered saline (PBS). Females were primed twice with 3.7IU/g hCG and then injected with an ovulatory dose (OvD) of 13.5 IU/ g BW (Body weight) hCG and 0.4 g/ g BW GnRH. Males were injected a single time with 10 IU/g BW hCG and 0.4 g/ g BW GnRH, 12 h after females received their OvD. In 2013, knowing the approximate time when females oviposited after hormone treatments, we tested the best time to induce amplexus and spermiation. Males were divided into 4 groups and injected at 4 different times: (a) 12 h before females OvD; (b) at the same time as OvD; (c) 12 h after OvD; (d) control injected with PBS. Results from 2012 indicated that oviposition was solely dependent on females receiving hormone treatments not males. However, in 2013 we found that the duration of amplexus significantly influenced oviposition (P>0.05), and males injected 12 h prior to females spent more time in amplexus than males injected at the same time or 12 h after the females received hormones. Promoting reproductive behaviors and synchronizing gamete deposition continues to be imprecise and may require more than exogenous hormones. The complexity of promoting breeding behaviors may require a closer assessment of the captive environment.

zoology↗

bioRxiv2017

Characterization Of Amylase And Protease Activities In The Digestive System Of Concholepas concholepas (Gastropoda, muricidae)

Concholepas concholepas (loco) is a carnivorous gastropod that inhabits the coast of Chile and Peru. Its fisheries showed a great importance in the past decades, however, now mainly relies on artisanal management of wild stocks. Feeding is one of the important factors that have restrained the establishment of large scale field rearing of loco. C. concholepas food preferences consist of mytilids and cirripeds, however its digestive physiology has not been studied and its digestive enzymes have not been yet characterized. The purification of amylase and protease from the digestive gland and the gland of Leiblein of C. concholepas were performed by ionic exchange chromatography (DEAE-cellulose), and substrate-PAGE indicated the presence of the amylase and protease in the fractions collected from the column. Amylase enzymatic assays showed its maximum activity at pH 7.0 and 50{degrees}C in the digestive gland. Protease on the other hand showed a great acidic activity, specifically at pH 3.0 in both organs, also at 50{degrees}C. Inhibition of the amylolytic activity was observed in the presence of EDTA, and metal ions like MnCl2, MgCl2, ZnSO4, while it was enhanced in the presence of CaCl2, NaCl, KCl. Protease inhibition assays were also performed evidencing mainly the presence of aspartic proteases and a low but not inexistent presence of serine proteases. Our results provide evidence of important proteolytic but also amylolytic activities present in the digestive system of loco, providing evidence that this mollusc has wider digestive capabilities than initially though, which could potentially lead to the development of alternative food diets.

biochemistry↗

bioRxiv2017

Global analysis of plasma lipids identifies liver-derived acyl-carnitines as a fuel source for brown fat thermogenesis

Cold induced thermogenesis is an energy demanding process that protects endotherms against a reduction in ambient temperature. Using non-targeted LC-MS based lipidomics, we identified plasma acylcarnitines as the most significantly changed lipid class in response to the cold. Here we show that acylcarnitines provide fuel for brown fat thermogenesis. In response to the cold, FFAs released from adipocytes activate the nuclear receptor HNF4 to stimulate the expression of genes involved in acylcarnitine metabolism in the liver. Conditional deletion of HNF4 in hepatocytes blocks the cold-induced changes in hepatic gene expression, lowering circulating long chain acylcarnitine (LCAC) levels, and impairing their ability to adapt to the cold. Finally, a bolus of L-carnitine or palmitoylcarnitine rescues the cold sensitivity seen with aging. Our data highlights an elegant mechanism whereby white adipose tissue provides FFAs for hepatic carnitilation to generate plasma LCAC as a fuel source for BAT thermogenesis.\n\nHighlightsO_LIBlood acylcarnitine levels increase in response to the cold.\nC_LIO_LIFFA mobilization in response to the cold activates hepatic HNF4 and stimulates genes involved in acylcarnitine metabolism.\nC_LIO_LIBrown adipocytes metabolize palmitoylcarnitine.\nC_LIO_LICarnitine administration improves thermogenic response in aged mice.\nC_LI\n\nETOCSimcox et al identified acylcarnitines as a novel source of energy for thermogenesis. In response to the cold, the liver activates a transcriptional program through the transcription factor HNF4, leading to increased acylcarnitine levels. They also find that aging mice have reduced acylcarnitine levels and an impaired thermogenic response in the cold. Increasing acylcarnitine levels in old mice increases their ability to adapt to the cold. Their studies discover a physiological role for acylcarnitines in thermogenesis.\n\nGraphical AbstractCold exposure stimulates the sympathetic nervous system to release noradrenaline (NA). Activation of {beta}3-adrenergic receptors stimulates FFA release and activation of the transcription factor HNF4 in the liver. This leads to increased gene expression of enzymes involved in acylcarnitine metabolism. The acylcarnitines are released in the blood to provide fuel for brown fat thermogenesis. These studies highlight the role of the liver in the thermogenic response.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC=\"FIGDIR/small/132241_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (80K):\norg.highwire.dtl.DTLVardef@1282891org.highwire.dtl.DTLVardef@17f7c7forg.highwire.dtl.DTLVardef@c6b637org.highwire.dtl.DTLVardef@1e4f40d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2017

Identification Of Cellular-Activity Dynamics Across Large Tissue Volumes In The Mammalian Brain

Tracking the coordinated activity of cellular events through volumes of intact tissue is a major challenge in biology that has inspired significant technological innovation. Yet scanless measurement of the high-speed activity of individual neurons across three dimensions in scattering mammalian tissue remains an open problem. Here we develop and validate a computational imaging approach (SWIFT) that integrates high-dimensional, structured statistics with light field microscopy to allow the synchronous acquisition of single-neuron resolution activity throughout intact tissue volumes as fast as a camera can capture images (currently up to 100 Hz at full camera resolution), attaining rates needed to keep pace with emerging fast calcium and voltage sensors. We demonstrate that this large field-of-view, single-snapshot volume acquisition method--which requires only a simple and inexpensive modification to a standard fluorescence microscope--enables scanless capture of coordinated activity patterns throughout mammalian neural volumes. Further, the volumetric nature of SWIFT also allows fast in vivo imaging, motion correction, and cell identification throughout curved subcortical structures like the dorsal hippocampus, where cellular-resolution dynamics spanning hippocampal subfields can be simultaneously observed during a virtual context learning task in a behaving animal. SWIFTs ability to rapidly and easily record from volumes of many cells across layers opens the door to widespread identification of dynamical motifs and timing dependencies among coordinated cell assemblies during adaptive, modulated, or maladaptive physiological processes in neural systems.

neuroscience↗

bioRxiv2017

The N-terminal domain of ALS-linked TDP-43 assembles without misfolding

TDP-43 forms inclusions in several neurodegenerative diseases, and both its N- and C-terminal domains are implicated in this process. We show that the folded TDP-43 N-terminal domain oligomerizes under physiological conditions and propose that, in full-length TDP-43, association between folded N-terminal domains enhances the propensity of the intrinsically unfolded C-terminal domains to drive pathological aggregation.

biophysics↗

bioRxiv2017

Omics-Based Hybrid Prediction In Maize

Accurate prediction of traits with complex genetic architecture is crucial for selecting superior candidates in animal and plant breeding and for guiding decisions in personalized medicine. Whole-genome prediction (WGP) has revolutionized these areas but has inherent limitations in incorporating intricate epistatic interactions. Downstream \"omics\" data are expected to integrate interactions within and between different biological strata and provide the opportunity to improve trait prediction. Yet, predicting traits from parents to progeny has not been addressed by a combination of \"omics\" data. Here, we evaluate several \"omics\" predictors -- genomic, transcriptomic and metabolic data -- measured on parent lines at early developmental stages, and demonstrate that the integration of transcriptomic with genomic data leads to higher success rates in the correct prediction of untested hybrid combinations in maize. Despite the high predictive ability of genomic data, transcriptomic data alone outperformed them and other predictors for the most complex heterotic trait, dry matter yield. An eQTL analysis revealed that transcriptomic data integrate genomic information from both, adjacent and distant sites relative to the expressed genes. Together, these findings suggest that downstream predictors capture physiological epistasis that is transmitted from parents to their hybrid offspring. We conclude that the use of downstream \"omics\" data in prediction can exploit important information beyond structural genomics for leveraging the efficiency of hybrid breeding.\n\nKey messageComplementing genomic data with other \"omics\" predictors can increase the probability of success for predicting the best hybrid combinations using complex agronomic traits.\n\nConflict of InterestThe authors declare that they have no conflict of interest.

genetics↗

bioRxiv2017

Activity-Dependent Control Of Inhibitory Interneuron Number In The Mammalian Cortex

Cortical networks are composed of excitatory projection neurons and inhibitory interneurons. Finding the right balance between the two is important for controlling overall cortical excitation and network dynamics. However, it is unclear how the correct number of cortical interneurons (CIs) is established in the mammalian forebrain. CIs are generated in excess from basal forebrain progenitors and their final numbers are adjusted via an intrinsically determined program of apoptosis that takes place during an early postnatal window. Here, we provide evidence that the extent of CI apoptosis during this critical period is plastic, cell type specific and can be reduced in a cell autonomous manner by acute increases in neuronal activity. We propose that the physiological state of the emerging neural network controls the activity levels of local CIs to modulate their numbers in a homeostatic manner.

neuroscience↗